Boston University
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Information Services and Technology
IS&T Papers
2004-2-17
Can Clinical Trials Requiring
Frequent Participant Contact Be
Conducted Over the Internet?
Results From an Online
Randomized Controlled Trial
Evaluating a Topical Ointment for
Herpes Labialis
Formica, Margaret
Gunther Eysenbach
Formica, Margaret, Karim Kabbara, Rachael Clark, Tim McAlindon. "Can Clinical
Trials Requiring Frequent Participant Contact Be Conducted Over the Internet?
Results From an Online Randomized Controlled Trial Evaluating a Topical Ointment
for Herpes Labialis" Journal of Medical Internet Research 6(1):e6. (2004)
http://hdl.handle.net/2144/3452
Boston University
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J Med Internet Res. 2004 Jan-Mar; 6(1): e6.
Published online 2004 February 17. doi: 10.2196/jmir.6.1.e6
PMCID: PMC1550589
Copyright © Margaret Formica, Karim Kabbara, Rachael Clark, Tim McAlindon. Originally published in the Journal of Medical Internet Research
(http://www.jmir.org), 17.2.2004. Except where otherwise noted, articles published in the Journal of Medical Internet Research are distributed under
the terms of the Creative Commons Attribution License (http://www.creativecommons.org/licenses/by/2.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited, including full bibliographic details and the URL (see
"please cite as" above), and this statement is included.
Can Clinical Trials Requiring Frequent Participant Contact Be Conducted Over the
Internet? Results From an Online Randomized Controlled Trial Evaluating a Topical
Ointment for Herpes Labialis
Margaret Formica, MSPH,
MPH1
1
Karim Kabbara, MSCIS,2 Rachael Clark, MD,3 and Tim McAlindon, MD,
Margaret Formica, Division of Rheumatology, Tufts-New England Medical Center, 750 Washington Street, Box 406, Boston MA 02111, USA,
Phone: +1 617 636 5651, Fax: +1 617 636 1542, Email: mformica@tufts-nemc.org.
Reviewed by Alex Jadad and Ron Marks
1Divisions of Rheumatology & Clinical Care Research, Tufts-New England Medical Center, Boston MA
2Office of Information Technology, Boston University School of Medicine, Boston MA 02118, USA
3Department of Dermatology, Brigham and Women's Hospital, Boston MA 02115, USA
02111, USA
Corresponding author.
Received August 14, 2003; Revisions requested September 29, 2003; Revised November 6, 2003; Accepted November 15, 2003.
This article has been cited by other articles in PMC.
Abstract
Background
The Internet has tremendous appeal for conducting randomized clinical trials and may be especially applicable to
trials requiring frequent participant contact. Trials of cold sore remedies, for example, often require daily clinic visits
during outbreaks, imposing substantial burden on participants. An Internet-based randomized clinical trial design may
reduce this burden, permitting frequent symptom reports with considerably less effort.
Objective
To evaluate the feasibility of a Web-based randomized clinical trial requiring frequent participant interaction, using a 6month, double-blind, randomized, placebo-controlled pilot trial of a topical ointment containing dioctyl sodium
sulfosuccinate (DSS) (Zilex; Meditech Pharmaceuticals, Inc, Scottsdale, Arizona, USA) intended for treatment of
recurrent herpes labialis. A secondary objective was to obtain preliminary data on effectiveness outcomes, to assist
in planning a fully-powered trial of DSS.
Methods
Adults with physician-confirmed herpes labialis were recruited to apply to the trial. Eligible applicants were
randomized to DSS or placebo, mailed to them upon enrolment with instructions to apply topically every 2 hours for
the duration of every cold sore outbreak. Participants were instructed to complete online questionnaires at 2-week
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intervals and, at the initiation of a cold sore, daily "outbreak questionnaires" until outbreak termination. Feasibility
outcome measures included trial participant characteristics, frequency of cold sores, participant retention and
adherence (to study medication), and data completeness. Treatment effectiveness outcome measures included
outbreak duration, days to crust formation, and pain.
Results
Of the 292 individuals applying, 182 screened eligible; 32 participants with confirmed herpes labialis enrolled in the
trial. 16 were randomized into the verum group and 16 into the placebo group. 29 (91%) participants completed the
trial. During the trial, 34 outbreaks were reported among 23 (72%) participants, resulting in a cold sore incidence rate
of 19.8 per 100 person-months of observation. Online data were available for 32 outbreaks; the absence of a
resolution date made it impossible to accurately calculate the duration of 12 (38%) outbreaks. Although the DSS
treatment group had a shorter mean outbreak duration (6.6 vs 7.7 days, P= .2) and fewer mean days to crust
formation (3.5 vs 4.9, P= .1), these differences did not reach statistical significance. The DSS group has statistically
significant lower mean pain scores (3.1 vs 7.6, P= .04), but participants in this group also consumed more
acetaminophen tablets than the placebo group (1.1 versus 0.5, P=.55). Adherence to medication was similar in both
groups: 7 (50%) of the verum group reported using the cream as directed compared to 6 (46.2%) in the placebo
group; ( P= .8).
Conclusions
We efficiently recruited participants and achieved high overall retention rates. However, participant adherence to the
daily outbreak visit schedules was low and only 7 (50%) participants used the cream as directed. These limitations
could be addressed in future Internet-based studies by using Personal Digital Assistants (PDAs), using reminder
devices, and providing incentives. By enhancing participant adherence, clinical trials requiring frequent participant
contact may be feasible over the Internet.
Keywords: Internet, randomized controlled trial, clinical trial, herpes labialis, dioctyl sodium sulfosuccinate
Introduction
Due to its access to vast segments of the population and its technological capabilities, the Internet has tremendous
appeal as a vehicle for conducting randomized controlled clinical trials (RCTs) [1- 4]. In previous work we found it
highly feasible to rapidly recruit individuals over the Internet into an online randomized controlled clinical trial of
glucosamine for knee osteoarthritis [5]. The Internet-based approach may be especially applicable to randomized
controlled clinical trial designs that require frequent participant contact. Trials of cold sore remedies, for example,
often require daily clinic visits during outbreaks, imposing substantial burden on participants [6]. While clinic visits
may represent the ideal patient evaluation, these frequent visits may hinder participant recruitment and retention. An
Internet-based randomized controlled clinical trial design could theoretically reduce this burden and permit frequent
symptom reports with considerably less effort.
The objectives of our study were to evaluate the feasibility of an Internet-based approach for testing a topical
ointment containing dioctyl sodium sulfosuccinate (DSS) (Zilex; Meditech Pharmaceuticals, Inc, Scottsdale, Arizona,
USA) for herpes labialis (oral herpes simplex, cold sores), and to collect preliminary outcome data for this potential
cold sore remedy. DSS has been shown to have in vitro efficacy against herpes simplex virus type 1 through
disruptive effects on the viral capsule [7]. In addition, Zilex contains benzocaine, a well-known anesthetic that has
been shown to be effective in pain reduction [8,9].
Methods
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Web Site Development
The study Web site was constructed on an independent server within the Boston University School of Medicine
domain. The Web pages were written in Hypertext Markup Language (HTML), Active Server Pages (ASP),
JavaScript, and Component Object Modeling interfaced with a Structured Query Language (SQL) Server database.
Microsoft Access [10] software was used to query the database and to create reports. The security of our site was
protected by a firewall and 128-bit secure socket layering encryption. In addition, we operated data-security protocols
that included automated error checking, limited password-protected access to the data interface and database,
permission levels, username-linked logging of all changes made in the database, participant tracking by ID number,
encryption of randomization codes, and screen time-outs.
The public area of the Web site described the study and solicited participants, with hypertext links to a consent form
and an eligibility-screening page. The password-protected private area of the Web site included pages where
participants could view utilities and access the study questionnaires. The Web site included a batching utility that (1)
sent e-mails to participants reminding them of their scheduled online "visits" and (2) included code that presented the
appropriate questionnaires to each participant when logging into the Web site at the time of these visits.
Design of the Randomized Controlled Clinical Trial
This was a 6-month randomized, placebo-controlled trial of a topical ointment in the treatment of herpes labialis. The
objective was to enroll 30 participants with a history of herpes labialis, randomize them to verum (Zilex) or placebo,
and follow them for cold sore outbreaks. Because of the 6-month follow-up period, participants had the opportunity to
report several cold sore outbreaks and the key emphasis of the trial was on the "outbreak." The primary outcome
measure was duration of outbreak, which was ascertained through daily outbreak questionnaires. This study was
approved by the Institutional Review Board at Boston University School of Medicine.
Recruitment and Eligibility
Adults with a history of herpes labialis were recruited through newspaper and e-zine advertisements directing them to
the trial Web site, which described the study and contained an eligibility questionnaire. Eligible applicants had to be at
least 18 years of age, take no immunosuppressives, report at least 4 cold sore outbreaks per year for more than 1
year, report a last-outbreak occurrence ≤ 6 months ago, and report at least moderately-severe external cold sores.
Applicants who screened eligible were asked to print, sign, and mail an informed consent form including a medicalrecords release. When medical records could not be obtained, the participant was contacted by a physician (TM) to
confirm the diagnosis of herpes labialis. The identity of all participants was authenticated by receipt of a signed
consent form. In addition, authentication of participant's identities was confirmed by receipt of medical records, or by
telephone.
Randomization, Medication Delivery, and Medication Application
Eligible authenticated applicants who completed a 2-week run-in phase were randomized in a double-blind manner to
either verum or placebo. Staff uninvolved with other aspects of the trial maintained the computer-generated
randomization list and labeled the tubes of study medication. The tubes, distinguishable only by a code number on
the label, were then provided to study staff. Tubes of study medication, along with an instruction guide, were sent to
participants by 2-day mail. Participants were sent an e-mail notifying them that the study medication was en route
and should arrive within 5 days. Participants were asked to notify us via the study Web site when they received the
study medication. Participants were instructed to apply the study medication at the first sensation of a cold sore
outbreak and continue to apply the medication every 2 hours until the cold sore healed completely.
Questionnaires
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Participants were asked to complete scheduled online questionnaires at 2-week intervals; these questionnaires
included information on the participant's cold sore history and remaining study medication.
At the initiation of an outbreak, participants were asked to complete daily online outbreak questionnaires, which were
date stamped and included a standard pictorial illustration of cold sore evolution (stages 1-6, and 0 indicating a
completely-healed cold sore; Figure 1), as well as questions on the number of clusters present, the location of the
cold sore, use of pain medication or other cold sore medications, and the degree of pain associated with the cold sore
(Likert scale 0-4) (see Figure 2 and Multimedia Appendix). E-mail reminders were sent to participants if they did not
complete a daily outbreak questionnaire during the course of an outbreak. A supplemental questionnaire was e-mailed
to participants at the completion of a cold sore outbreak; this questionnaire asked about the length of the outbreak,
how long ago the outbreak occurred, adherence to study medication, and satisfaction with the study medication.
Outcome Measures
Outcome measures pertaining to the evaluation of the feasibility of conducting the trial online are descriptive in nature
and include characteristics of the trial participants, frequency of cold sore outbreaks, participant retention and
adherence to the study medication, and completeness of data.
Treatment-effectiveness measures included total duration of outbreak, days to crust formation, and pain. Total
duration of outbreak was defined by subtracting the date of the initial online outbreak questionnaire from the date of
the outbreak questionnaire that indicated the cold sore had healed completely. Days to crust formation was defined
by subtracting the date of the initial online outbreak questionnaire from the date of the online questionnaire in which
the participant first reported that the cold sore had reached at least stage 5. Pain was defined as the sum of the daily
pain scores for the duration of the outbreak. Additional outcome measures included sum of the daily scores for cold
sore stage, sum of the number of clusters reported daily for the duration of the outbreak, and the sum of
acetaminophen tablets taken over the duration of the outbreak.
Adverse Events
Participants were asked to report any adverse events via a form on the Web site, e-mail to the study staff, or a tollfree telephone line. The daily online outbreak visit questionnaire also allowed participants to report comments on the
feel, taste, or performance of the study cream. In addition, participants were asked in the supplemental e-mailed
questionnaire if they had any problems with the study cream.
Statistical Analysis
We used an intention-to-treat analytic approach. In cases where the total duration of an outbreak could not be
calculated because the endpoint of the outbreak was unclear or the participant informed us of the outbreak only after
it occurred (N = 2), we imputed a duration based on the mean duration of all of the other outbreaks. This method was
used for the days to crust formation, sum of the daily pain scores, sum of the daily stage scores, sum of the number
of clusters reported daily, and sum of acetaminophen tablets taken over the duration of the outbreak. Additional
analyses were conducted excluding outbreaks for which imputation was necessary.
Baseline characteristics of the treatment groups were compared using Fisher exact tests and t tests. Differences
between the treatment groups were evaluated using Wilcoxon rank sum tests for continuous outcome measures and
Fisher exact tests and chi-square tests for categorical outcome measures. Generalized linear models were used to
test for differences after adjusting for gender and age.
Results
Figure 3 shows the CONSORT flow diagram [11] of the trial from application to completion. Of the 292 individuals
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who applied to the trial, 182 screened eligible, and 40 mailed signed consent forms. Ultimately, 32 participants with
confirmed herpes labialis completed the 2-week run-in phase and enrolled in the trial, verum (N = 16) or placebo (N =
16).
The mean age of participants was 43 (range, 20-72). 23 (72%) were female and all participants were Caucasian.
Baseline characteristics of the participants by randomized group are displayed in Table 1. The groups were similar
with respect to geographic region, but differed with respect to age and gender, although these differences did not
reach statistical significance on a 5% level.
Three participants were lost to follow-up, resulting in 29 (91%) who completed the trial. During the course of the trial,
34 outbreaks were reported among 23 (72%) participants. After accounting for losses to follow-up, the cold sore
incidence rate was 19.8 per 100 person-months of observation. Two outbreaks occurred while participants were on
vacation, leaving 32 outbreaks for which online data were available.
Figure 4 illustrates the completeness of data, as well as self-reported stage for the 32 cold sore outbreaks for which
we had online data. Due to missing data at the end of the outbreak, total duration of outbreak could not be calculated
for 12 (38%) and days to crust formation could not be calculated for 10 (31%) of the outbreaks. The stages for 14
(44%) outbreaks followed a normal cold sore evolution.
Results adjusted for gender and age did not differ substantially from unadjusted results, therefore, only the former are
presented. The verum group had a shorter mean duration of outbreak, fewer mean days to crust formation, and lower
mean sum of clusters than the placebo group, but none of these differences reached statistical significance. The
verum group had a statistically significant ( P=.04) lower mean sum of daily pain scores than the placebo group (
Table 2). The mean sum of acetaminophen tablets taken over the course of the outbreak was slightly higher in the
verum group compared to the placebo group. Analyses that excluded outbreaks for which imputation was necessary
had similar results, but the magnitude of difference between the treatment groups was greater.
Adherence to the study medication was similar in both groups, 7 (50%) of the DSS group reported using the cream at
least every 2 hours compared to 6 (46.2%) in the placebo group; ( P= .84). Most participants reported using the
cream at least every 4 hours (78%) and all participants reported using the cream at least once per day during an
outbreak. For 2 outbreaks, participants had not yet received their study medication in the mail. Both groups were
similar with respect to belief that they were taking the active cream, that the cream made their cold sores much
better, helped abort their outbreaks, and worked as well or better than the creams used in the past (Table 3).
No adverse events were reported during the course of the trial via the adverse-event reporting form on the Web site,
e-mail, or phone. However, several participants reported in questionnaires that:
the cream tingled/burned on application: DSS (n = 1), placebo (n = 3)
was numbing: DSS (n = 5), placebo (n = 1)
was gritty: DSS (n = 1), placebo (n = 1)
dried the lips: DSS (n = 1), placebo (n = 0)
tasted bad: DSS (n = 1), placebo (n = 2)
did not work: DSS (n = 0), placebo (n = 2)
slid off the lip: DSS (n = 1), placebo (n = 0)
"made the blisters spread more": DSS (n = 1), placebo (n = 0).
Discussion
The primary goal of this study was to evaluate the feasibility of conducting a clinical trial on the Internet that focused
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on outbreaks and required frequent participant contact. Certain aspects of this trial design proved to be robust.
Participant recruitment was relatively easy; the interactive nature of the Web site with an eligibility questionnaire
reduced the burden on the investigators of screening applicants, and we were able to exceed our recruitment goal in a
short period of time (6 months). Overall participant retention in the trial was high; 29 (91%) of participants completed
the trial. In addition, the reduction in pain seen in the verum group compared to the placebo group lends support to
the internal validity of this approach, as Zilexcontains benzocaine, an anesthetic shown to be effective in pain
reduction [8,9].
While we found recruitment to be unproblematic and overall participant retention high, there were several aspects of
this clinical trial design that need refinement. While it is unclear whether this experience differs from traditional clinical
trials [6], there were a number of outbreaks for which it was difficult to assign a total duration due to missing data.
Many of the missed visits occurred during weekends and holidays. This pattern indicates the possibility that many
participants were accessing the trial Web site from work, and may not have had access to the Internet at home.
Future trials of this nature may benefit by requiring participants to have Internet access at home. In addition, our trial
participants did not receive any compensation. It is conceivable that some form of compensation might improve
compliance in this respect.
Another concern with the results of the trial was incomplete adherence to the study medication. It is unclear whether
participants in a traditional clinic setting would have been more likely to use the study medication as directed. Poor
adherence to study medication in clinical trials can have detrimental effects on the evaluation of safety and efficacy.
On the other hand, the adherence rate found in this trial may be reflective of adherence to the medication in the
general population and could, therefore, provide a valid evaluation of effectiveness.
Limited generalizability may be a potential limitation of an Internet-based trial design. Our participants were Internet
users and might not be representative of all individuals with cold sores. While this could theoretically influence the
generalizability of our findings, it should not impair the validity. Of course, hospital-based or clinic-based trials face
similar problems in that their participants are frequently highly selected.
One of the primary benefits of an Internet-based design for a clinical trial requiring frequent participant contact is the
reduced burden on participants. An alternative approach would be to augment this system using electronic data
capture through wireless personal digital assistants (PDAs) [12].
As a feasibility study, this endeavor has been highly informative. In particular, it appears that even with the reduced
participant burden inherent in the Internet-based approach, the goals of daily online visits and adherence to an every2-hours dosing schedule pose significant challenges. Based on our experiences, we make the following
recommendations for future such trials: (1) mail a supply of (masked) active and placebo to each participant at
enrolment, (2) randomize outbreaks rather than participants, (3) use the Internet as a portal enhanced by wireless
PDAs for frequent data capture, (4) program the PDAs to perform a reminder function for medication adherence, and
(5) consider providing an incentive.
Acknowledgments
This study was funded by Meditech Pharmaceuticals, Inc, PMB 382, 10105 E. Via Linda, Suite 103, Scottsdale, AZ
85258, USA. Thanks are due to Jeremiah Fletcher for his Web site development and graphics expertise.
Abbreviations
DSS Dioctyl Sodium Sulfosuccinate
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PDA Personal Digital Assistant
Multimedia Appendix
Screenshots of the web-based interfaces for trial participants:
Footnotes
Conflicts of Interest: None declared.
References
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10. Microsoft Access [computer program] [2004 Jan 5]. http://www.microsoft.com/
11. Altman D G, Schulz K F, Moher D, Egger M, Davidoff F, Elbourne D, Gøtzsche P C, Lang T. CONSORT GROUP (Consolidated
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Figures and Tables
Figure 1
Standard Pictorial Illustration of Cold Sore Stages as Part of the Online Outbreak Questionnaire
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Figure 2
Part of the Outbreak Questionnaire (see also Multimedia Appendix)
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Figure 3
CONSORT flow diagram
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Table 1
Baseline characteristics of trial participants
P*
Participants Receiving DSS (N = 16)
Participants Receiving Placebo (N = 16)
N (%)
N (%)
9 (56.3)
14 (87.5)
.11
Northeast
7 (43.8)
6 (37.5)
.42
Southeast
2 (12.5)
5 (31.3)
Midwest
5 (31.3)
2 (12.5)
West
2 (12.5)
3 (18.8)
Mean age (SD)
39.8 (10.5)
46.2 (13.4)
Median age (IQ range)
44.5 (15)
51.5 (14)
Female
Region of the United States
.14
P values are based on 2-tailed Fisher exact tests for categorical outcome measures and a 2-tailed, unpaired t test with 30 degrees of freedom for
mean age.
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Figure 4
Duration and daily stage information for 32 cold sore outbreaks for which online data was available. Outbreaks 1-15
were treated with DSS, outbreaks 16-32 were treated with placebo. ? = missing data
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Table 2
Means of duration of outbreak, days to crust formation, sum of pain scores, sum of stage scores, sum of clusters,
and sum of acetaminophen use by treatment group; adjusted for gender and age
Outbreaks (N = 15)
Outbreaks (N = 19)
for Participants Receiving DSS
for Participants Receiving Placebo
P
Total duration of outbreak (days)
6.6
7.7
.24
Days to crust formation
3.5
4.9
.10
Sum of daily pain scores
3.1
7.6
.04
Sum of daily stage scores
17.5
17.9
.95
Sum of clusters
4.7
6.8
.24
Sum of acetaminophen tablets
1.1
0.5
.55
Total duration of outbreak (days) *
6.3
8.2
.21
Days to crust formation†
3.5
5.0
.14
After exclusion of outbreaks requiring imputation
*
Six and 8 outbreaks were excluded from the verum and placebo groups, respectively.
†
Five and 7 outbreaks were excluded from the verum and placebo groups, respectively.
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Table 3
Frequencies, percentages, and 2-tailed Fisher exact tests of categorical outcome measures
DSS (N = 14)
Placebo (N = 13)
N (%)
N (%)
Reported use of cream as directed
7 (50.0)
6 (46.2)
.84*
Reported cream made cold sores "much better"
8 (57.1)
9 (69.2)
.69
Reported cream helped abort outbreak
9 (64.3)
10 (76.9)
.68
Reported belief that they are taking active cream
13 (92.9)
10 (76.9)
.33
Reported cream worked "as well or better than creams used in past"
10 (76.9) †
12 (92.3)
.59
*
Chi-square test (χ 21= 0.04).
†
Information was missing for 1 outbreak.
P
Articles from Journal of Medical Internet Research are provided here courtesy of
Gunther Eysenbach
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